The present invention relates to beads which are useful as packed bed and fluidized bed support materials for adsorption and chromatography, and methods of making these support materials.
Modern preparative and analytical solid phase adsorption and chromatography techniques call for improved stationary phases exhibiting high selectivity, large capacity, high mechanical resistance, and high chemical compatibility. These properties, defined by the characteristics of the solid matrix, have evolved with the development of adsorbent media, from soft organic material to semi rigid packing and then to rigid mineral solid phases.
Large capacity, and the ability to control pore size as well as chemical functionalization, has led to the development of many types of soft organic sorbents, based on polysaccharides (dextran, agarose, cellulose) or on weakly crosslinked synthetic materials (dilute polyacrylates, dilute polymethacrylates, dilute polyacrylamide derivatives). These materials have been employed in many applications, such as ion-exchange, gel filtration, and affinity chromatography, but they have always suffered from limited mechanical stability unfavorable for utilization at large scale or high velocity.
Additionally, when mixed in solvents (e.g. 95% ethanol) or in high salt concentration solutions, or when submitted to moderate temperatures (e.g. 35-50xc2x0 C.) or to mechanical stresses (e.g. pressures of 1.5-3 bar), the properties of these soft organic adsorbents are altered such that their specificity or the efficacy of the separation is reduced or even lost. These undesirable mechanical and functional modifications include pore size reduction, network shrinkage, alteration of bead sphericity and chemical degradation. Additionally, the low density of soft organic polymers makes it difficult to use them in situations where the solid phase must be separated from the liquid phase. This is particularly the case for stirred tank solid phase adsorption, in which the beads must be collected by sedimentation. These organic particles are also difficult to handle in fluid and expanded beds due to the low density difference between the beads and the liquid in which they are suspended.
Semi-rigid organic materials, such as synthetic organic polymers (e.g. crosslinked polyacrylamide derivatives, crosslinked polystyrene, or crosslinked polystyrene-divinylbenzene copolymers) as well as crosslinked natural polymers (e.g. crosslinked agarose) have also been used as sorbents for liquid chromatographic applications. These polymers possess improved mechanical resistance over soft hydrophilic organic materials, but their use is restricted to the low to medium pressure range, which is prejudicial to maximum process velocity and bed height. Operating at high velocity is often advantageous to improve the column productivity or, in some instances, to reduce the processing time of labile molecule. Semi-rigid packing materials subjected to a low or medium hydrostatic pressure can be deformed to such an extent that the packed bed interstitial volume is contracted. This reduction in the bed permeability induces a further increase in the pressure drop, followed by clogging of the column.
Similarly, the low density differential between the aqueous solutions usually used in liquid chromatography and organic polymer based chromatographic media precludes their use for fluidized bed applications. In fluidized bed applications, upward liquid speeds for a given bed expansion depend on particle density and particle diameter. There is little benefit to compensating for low density by increasing the particle diameter, because there is a concomitant increase in the characteristic diffusion length within the bead that constrains the mass transfer efficiency, and hence the productivity of the media.
Therefore, there is a need to provide relatively small porous particles which retain their shape, their chemical and mechanical properties in specific environments useful for biomolecule separation in column as well as in suspension, and which offer a substantial density difference with liquids used in adsorption and chromatography.
To circumvent the compressibility and related drawbacks of organic materials, mineral based sorbents have been developed. These sorbents are based on porous mineral materials, on the surface of which chemical functions are grafted for chromatographic application. Porous silica material, the most popular mineral chromatographic solid phase, is relatively easily modified to a desired surface area, pore volume and pore size.
The binding capacity of conventional mineral grafted silica is directly related to the internal surface area available for chemical modification. The trend, therefore, has been to select high specific surface area material to obtain the highest chemical grafting ratio (see, Unger, K., Porous Silica, Elsevier, Amsterdam-Oxford-New York (1979)). However, due to the inverse relationship between specific surface area and pore diameter, a compromise between pore size and specific surface area must be reached, especially for large solute adsorption applications. A silica with a large surface area yields a low pore diameter, which hinders or even prevents the diffusion of large solutes into the pores and causes incomplete surface utilization for binding (Mohan, S. et al., Biotechnology and Bioengineering, 40, 549-563 (1992)). On the other hand, a silica bead having a pore diameter large enough for unhindered large molecule diffusion possesses a reduced surface area and therefore a low grafting ratio and a low binding capacity (Kopaciewicz, W. et al., Journal of Chromatography, 409, 111-124 (1987)).
To solve the specific problem related to the separation of large molecules, particularly proteins and nucleic acids, silicas with the pore volume filled by weakly crosslinked natural and synthetic hydrogels have been described (U.S. Pat. Nos. 4,673,734 and 5,268,097). With such media, large pore silica with low surface area is converted to a high capacity media by intraparticle polymerization of functionalized monomers and a crosslinking agent or by introducing polysaccharides that are crosslinked in place. It has been demonstrated that the sorptive capacity of this type of packing material is only dependent on the mineral matrix pore volume. Unlike surface grafted or polymer coated silica, the surface area of this media does not impact directly the binding capacity. The sorptive capacity is a function only of the amount of hydrogel present within the pores, and therefore the pore volume plays a primary role. The bead porosity must therefore be as large as possible, to increase the volume of the hydrogel on which the sorption of macromolecules occurs. However, like classical silica based material, a diminution of capacity is observed for low pore diameter matrixes, due to steric hindrance for large molecular weight solutes, which are unable to access the totality of the gel filled pore volume. For example, U.S. Pat. No. 5,268,097 discloses that at a constant pore volume of 1 mL/g, a 40% decrease in bovine serum albumin binding capacity was observed when the pore diameter was reduced from 3000 to 300 xc3x85.
In this composite stationary phase, the rigid skeleton provides mechanical strength enabling operation at high flow rates without compression, while the soft gel provides the adsorption sites. This approach has been successful in providing a variety of large protein binding capacity media, he functionality of which depend on the hydrogel composition (Boschetti, E., Journal of Chromatography A, 658, 207-236 (1994); Horvath, J. et al., Journal of Chromatography A, 679, 11-22 (1994)). However, silica shows a high sensitivity to alkaline conditions that precludes its utilization in applications requiring the use of a base. However, basic conditions are required for the large majority of biomolecule separation processes, as they require an alkaline pH treatment either for compound elution, or for sorbent cleaning. As a result, the use of silica-based media is problematic in such processes.
The sensitivity of silica-based media to alkaline conditions can be avoided to some extent by the use of large pore diameter media. With a large pore diameter, and therefore a low surface area, the sensitivity of silica material to caustic solutions is reduced, since the sensitivity is a surface-area dependent phenomenon. Hydrothermal treatment is a classical means to increase the average pore diameter of silica materials and concurrently to reduce the specific surface area (Unger, 1979). However, additional improvements are necessary to enhance the silica stability to repetitive alkaline treatments.
Many attempts have been made to increase the pH stability of silica packing. For example, U.S. Pat. Nos. 4,648,975 and 4,600,646 describe methods for cladding a porous silica with an alkali-stable metal oxide layer. Although these treatments contribute to an enhancement of the alkaline stability of silica based material, they are still insufficient with regard to packing length life and contamination of column effluent by leachable silicate.
More recent work has attempted to produce alkaline stable porous mineral oxide based media, such as titania (titanium dioxide) or zirconia (zirconium dioxide), that would advantageously replace porous silica as a solid matrix, due to their chemical inertness in both low and high pH environments. However, none of these porous materials, as of today, possess physical characteristics compatible with the hydrogel-filled porous packing concept.
For example, U.S. Pat. Nos. 5,015,373 and 5,271,833 describe spherical beads of zirconia stable in about pH 14 solutions. These beads are obtained, for example, by a sol-gel method that consists of emulsifying an aqueous colloidal zirconia sol in a water immiscible liquid. The liquid is chosen so that it extracts the water from the pellets to form gelled spherules. After gelification, the spherules are hardened by calcination at temperature ranging from 400 to 900xc2x0 C. The mineral oxide is then coated with a hydrophobic polymer, such as polybutadiene.
The zirconia particles produced with this process have a relatively large surface area, a low mean pore diameter and a medium porosity, as described in U.S. Pat. No. 5,015,373. Increasing the firing temperature from 400 to 900xc2x0 C. decreases the surface area from 142 to 14 m2/g, increases the pore diameter from to 40 to 220 xc3x85, and decreases the internal porosity from about 50 to 30% of the total bead volume.
After functionalization with polymers, these media are adequate only for small size molecule purification. They would not be adequate as substrates for a polymer filled based packing approach, due to their low porosity and small pore dimension. Hindered intraparticle diffusion of macromolecules such as typical biomolecules is expected with such material.
Pore size larger than about 500 xc3x85 are required for unhindered protein diffusion in gel filled pore packing. Moreover, the firing process, described in the aforementioned patents, contributes only slightly to the increase of the pore diameter and to the detriment of the bead porosity. Consequently, binding capacities of gel filled beads based on this process would reach only modest values, due to steric hindrance (low pore diameter) and reduced pore volume.
In addition, mineral oxide surfaces exhibit various types of interactions with proteins (electrostatic, van der Waals, Lewis acid-base), that can alter the quality of a separation or even denature the biomolecule. Therefore these activities must be suppressed or masked when dealing with grafted or polymer coated phases. Thus, there are definite advantages in utilizing a low specific surface area mineral oxide in order to minimize non-specific interactions that reduce the specificity of the purification.
U.S. Pat. No. 5,128,291 describes the production of zirconia or titania particles by spray-drying a slurry of zirconia or titania powder to which a soluble compound of a metal (called the binder), such as titanium or zirconium nitrate or sulfate, is added. This soluble compound decomposes during the spray-drying phase and cements the subparticles.
The initial diameter of elemental particles (called ultimate particles in the U.S. Pat. No. 5,128,291) used for the preparation of the final porous beads determines the final size of the pores. U.S. Pat. No. 5,128,291 indicates that the larger the ultimate particles, the larger the pore diameter. Examples 1 and 2 report that beads obtained by spray-drying followed by a 500xc2x0 C. calcination show a pore diameter of about 2000 xc3x85, a specific surface area of about 18 m2/g and a porosity of about 45%, using ultimate particles of 2000 xc3x85.
In other words, stronger bonds between the elemental particles may be achieved by using higher sintering temperatures (Nelson, T. et al., Ind. Eng. Chem. Res., 27, 1502-1505 (1988)). While the increase in the sintering temperature will in fact cement more tightly the particles, it will be prejudicial for the porosity. High temperature sintering of such a conglomerate of elemental particles will give lower pore volume as a result of a volume collapse related to the melting phenomena between subparticles.
It is also well known that treatment of some mineral oxides at high temperatures is responsible for crystallographic changes which may adversely impact the mechanical stability of the final product.
For example, zirconia may exist at room temperature in an amorphous form as well as any of three crystallographic forms: monoclinic, tetragonal and cubic. The cubic form is the highest energy form and is thermodynamically less stable than the two other forms at room temperature. The monoclinic form is the most stable conformation at room temperature. On cooling across the transformation temperature, from the tetragonal to the monoclinic phase, the volume of zirconia grains increases by 3 to 5%. This change in volume produces strains in the matrix that are responsible for the development of cracks. These structural defects are critical for the product stability (Koller, A., Structure and Properties of Ceramics, Elsevier, Amsterdam, London, New York, Tokyo (1994)).
The strength of mineral oxide matrixes produced as described in U.S. Pat. No. 5,128,291 cannot be reinforced by a higher sintering treatment due to the deleterious effect of phase transformations combined with a pore volume shrinkage. Both effects would prohibit the use of such materials in processes requiring high attrition resistance or high binding capacity.
Additionally, the use of binders, such as zirconium sulfate, has been criticized (Nawrocki, J. et al., Journal of Chromatography A, 657, 229-282 (1993)) because sulfates may not be removed by the relatively low calcination temperature suggested in U.S. Pat. No. 5,128,291, and may produce very acidic sites on the surface of final particles that may interfere with the quality of the chromatographic separation.
As a means to reduce the effect of high temperature on pore volume reduction, sodium chloride has been described as an additive prior to the sintering of porous silica (Unger, 1979). This technique consists of filling the porosity with a high-temperature-melting salt, such as sodium chloride, and calcining at a temperature below the melting point of the salt. This process results in an increase in mean pore diameter, by melting the narrower pores of silica, with only a slight decrease in the pore volume. This methodology has been recently applied to low pore diameter zirconia beads (Shalliker, R. et al., J. Liq. Chrom. and Rel. Technol., 20(11), 1651-1666 (1997)), allowing the production of about 400 xc3x85 beads. However, this controlled sintering process is difficult to operate, and requires prohibitive washing with water and solvent to eliminate the salt entrapped in the porosity which is, moreover, lost.
The present invention relates to new mineral oxide beads exhibiting superior chemical stability at any pH together with high porosity, low surface area, high mean pore diameter, high mechanical stability and attrition resistance. The beads are suited for transformation into polymer-filled pore-based sorbents. Moreover, they show a high density that facilitates the packing of fixed-bed columns, increases the particle sedimentation velocity in batch, and permits the use of high velocity in fluidized-bed operations.
Specifically, the present invention encompasses mineral oxide beads of a tetravalent metal such as zirconia, hafnia or titania, which have a pore volume which exceeds 40% of the bead volume. The invention also encompasses the mineral oxide beads which have pores filled with a hydrogel polymer.
The present invention also relates to a new method of increasing the pore volume of mineral oxides by the use of mineral pore inducers. When the resulting materials are fired at high temperature to sinter the mineral architecture, the presence of mineral pore inducers also stabilizes a crystallographic form to prevent any grain growth and concomitant cracks due to crystallographic phase transformation. As a result of the high sintering temperature and absence of crystallographic phase transformation, particles with high mechanical stability and attrition resistance are obtained, while preserving a high pore volume. This is accomplished by a process in which beads are formed from a mixture of a mineral oxide of a tetravalent metal, a macropore inducing agent and optional binders. The macropore inducing agent is an oxide or a salt of a trivalent metal such as aluminum, gallium, indium, scandium, yttrium, lanthanum, actinium, or a rare earth metal.
The present invention additionally encompasses the use of the novel mineral oxide beads described herein in solid phase adsorption and in chromatographic applications.
The present invention provides novel compositions of mineral oxide porous particles as well as methods to produce and use the compositions. The compositions of the present invention can be small discrete beaded particles as well as irregular shaped particles, showing high pore volume and high mechanical and chemical stability. Because of their stability and high porosity, they are particularly useful in packed bed, fluidized bed or stirred batch adsorption or chromatographic separation for large macromolecules. In particular these particles are suitable for transformation into gel-filled pore-packing sorbents.
The present invention utilizes a surprising and useful property found when preparing aqueous suspensions of metal oxide microparticles, such as zirconia, titania and hafnia, mixed with salts or oxides of other elements that possess a different valence, such as rare earth salts or aluminum salt. For example, mixing zirconium oxide (ZrO2) with yttrium oxide (Y2O3) or with yttrium nitrate Y(NO3)3 results in the formation of a viscous suspension which is used to make a macroporous material by agglomeration. It was unexpectedly discovered that the resulting materials exhibit a significantly higher porosity and mean pore diameter than materials composed of zirconium oxide alone. Moreover, the macroporosity was found to be proportional to the amount of the macropore inducing mineral agent introduced in the initial suspension.
Although it is not well understood why, combinations of tetravalent metal oxides, such as titanium oxide (TiO2), zirconium oxide (ZrO2) and hafnium oxide (HfO2), with trivalent metal salts and oxides, results in the formation of unstable suspensions which, after agglomeration to form spherical or irregular particles, show macroporosity and large pore sizes. This porosity and macropore size is greater than that obtained in the absence of such mineral macropore inducers.
The mineral oxide is an oxide of a tetravalent metal, preferably titanium, zirconium or hafnium. The mineral oxide can also be a mixture of two or more such tetravalent metal oxides. Preferably, the mineral oxides are in the form of a powder, and most preferably a powder with a particle size of 0.1 to 10 xcexcm.
The trivalent metal can be used in the form of an oxide, a salt, or mixtures of oxide and salt. A particularly preferred salt is nitrate. The metal can be any metal which exhibits a +3 valence, such as, group IIIB metals, rare earth metals, and the like. Preferred trivalent metals are aluminum, gallium, indium, scandium, yttrium, lanthanum, cerium, neodymium, erbium, ytterbium, and actinium.
Also included within the scope of the present inventions are compositions in which the trivalent metal oxide or salt is a mixture of two or more such oxides or salts. The terms xe2x80x9cmacropore inducersxe2x80x9d, xe2x80x9cpore inducersxe2x80x9d or xe2x80x9cpore inducing mineral agentxe2x80x9d as used herein refer to trivalent metal oxides or trivalent metal salts, as well as mixtures of two or more such trivalent metal oxides or trivalent metal salts. Such mixtures include salt/oxide mixtures, salt/salt mixtures and oxide/oxide mixtures of the same or different trivalent metals.
We have also discovered that the presence of mineral pore inducers also results in the unexpected and interesting property that only a limited pore volume reduction is observed when firing the compositions at very high temperatures. In contrast, metal oxide beads obtained without the benefit of the use of the pore inducers of the present invention yield low pore volumes when fired at very high temperatures, due to a severe reduction of pore volume resulting from the firing process.
Additionally, mineral pore inducers can be chosen so that they stabilize a crystalline form of the mineral oxide and avoid grain growth and cracking of the final material.
Optionally and preferably, an agent that induces particle agglomeration to make a beaded final material, such as an agglomeration promoting material or a binder may be included. The agglomeration promoting materials or binders can be salts of trivalent or tetravalent metals, and can contain the same tetravalent or trivalent metals used as the mineral oxide bead constituent or the pore inducing agent, or a different trivalent or tetravalent metal. In a preferred embodiment, the binder comprises a mixture of nitrates, including a tetravalent metal nitrate and a trivalent metal nitrate. For example, when zirconium oxide is used as a mineral oxide bead constituent and cerium oxide is used as a pore inducing agent, it is convenient to use a mixture of zirconium nitrate and cerium nitrate as a binder. Other suitable binders include materials which form mineral hydrogels that can encapsulate mineral oxide elemental particles, for example silica gels. A mineral hydrogel may also be used in combination with one or more additional binders.
The mineral composite oxides of the present invention are good porous materials for the preparation of sorbents used in solid phase adsorption and chromatography. They can, for instance, be filled with soluble polymers that are crosslinked in place as described in U.S. Pat. No. 4,673,734, or filled with monomers that can be copolymerized in place as described in U.S. Pat. No. 5,268,097.
According to the present invention, composite mineral oxides with enhanced pore volume are made by preparing a liquid suspension of a tetravalent mineral oxide. The liquid portion of the suspension can be water, or any other appropriate solvent. The mineral oxide should be in the form of a powder, with a particle size of between about 0.1 to 10 xcexcm, the particular particle size chosen depending on the desired pore size of the porous particles. This suspension is mixed with one or more pore inducing mineral agents. The suspension optionally also contains one or more binders.
In a typical composition which includes one or more metal oxide or salt binders, the binders are first mixed in a liquid such as water, then the mineral oxide and the pore inducing agent are added while stirring, producing a suspension. The stirring should be gentle, to avoid introducing air bubbles into the mixture.
The amount of pore inducing agent which is used in the initial suspension is roughly proportional to the amount of mineral oxide used. In the final product, the oxide of the tetravalent metal will constitute 50 to 99% of the final particles, with the remaining 1 to 50% made up of pore inducers and optional binders. In the initial suspension, however, the mineral oxide particles, the major constituent of the porous beads, are at a concentration of 10 to 95% by weight, based on the total weight of components used. More preferably, the mineral oxide should be 20-60% by weight. The pore inducing agent concentration is between 5-50% by weight. The optimal concentration varies, depending on the nature of the specific compounds used. The concentration of the agglomeration promoting material (binder) is between 0-20% by weight, and also depends on the nature of the binders. Optionally, organic compounds may also be added to the initial suspension in order to alter the viscosity of the solution.
The suspension containing all the desired components is then used to form beads. A variety of techniques well known in the art, such as spray drying, emulsion-polycondensation and sol-gel processes (as described, for example, in U.S. Pat. No. 5,015,373) can be used to effect the agglomeration of the compositions described in the present invention.
Once the elemental particles are agglomerated into a beaded shape they are heated at high temperature to stabilize the architecture of the porous mineral bead by partial fusion of the elemental particles. The heating rate, the calcination temperature and the soak time used depend on the nature of the mineral oxides and the mineral pore inducers. A controlled sintering is desirable in order to obtain stronger particles without elimination of the porosity. Typically, temperatures between 800 and 1400xc2x0 C., for a duration of 1 to 10 hours and with a heating rate ranging between 1 to 100xc2x0 C./hour are used. A sequential calcination treatment can also be used, to first remove volatile components such as water, organic materials, nitrates and the like, then to sinter the elemental particles.
The fired beads are then cooled to room temperature, and subsequently washed with, for example, acidic, alkaline, neutral or diluted hydro-organic solutions. The particles can optionally be subjected to a sieving step to adjust the particle size distribution, as desired.
In another feature of the present invention, the pore inducing agent can also act as a crystal phase stabilizer so as to eliminate the transition from one crystalline structure to another, and the accompanying volume change that would lead to cracking of the product.
Typical pore volumes obtained by such process are between 40 to 70%, and can be between 50 to 70%, of the total bead volume.
These beads can be used as base porous materials for the preparation of sorbents or chromatography beads by introducing within the large pore volume a hydrogel with predetermined properties. The large pore volume obtained with the product and the process of obtaining the mineral beads allows the introduction of large amounts of hydrogel into the particle cores, and therefore the binding capacity of the final sorbent is enhanced.
Organic hydrogels within the beads can be obtained by introducing linear hydrophilic, hydrophobic, or amphiphilic soluble organic polymers, or mixtures thereof, which are then crosslinked in place. Alternatively, the hydrogel filling can be accomplished by introducing solutions of monomers, which are then copolymerized in place. Both routes result in the formation of three-dimensional insoluble hydrogels that fill completely the pore volume of the mineral porous beads.
The linear soluble organic polymers can be natural or synthetic polymers. Suitable natural soluble polymers can include, but are not limited to, polysaccharides, such as agarose, dextran, cellulose, chitosan, glucosaminoglycans and their derivatives. Among synthetic soluble polymers, polyvinyl alcohol, polyethyleneimines, polyvinylamines, polyaminoacids, nucleic acids and their derivatives, for example, are suitable.
The synthetic and/or natural polymers are then crosslinked in place by known chemical and physical means, such as by using chemical bifunctional or polyfunctional crosslinkers such as, but not limited to, bisepoxy reagents, bisaldehydes, and the like.
The pore filling polymers can also comprise hydrophobic or hydrophilic networks obtained by total copolymerization of monomers. The polymeric or copolymeric structures can be obtained under specified conditions. In the case of polymers obtained by copolymerization within the pore volume, the impregnation solution contains monomers from different families such as acrylic monomers, vinyl compounds and allyl monomers or mixtures thereof. Typical monomers include, but are not limited to:
aliphatic ionic, non-ionic and reactive derivatives of acrylic, methacrylic, vinylic and allylic compounds, such as acrylamide, dimethylacrylamide, trisacryl, acrylic acid, acryloylglycine, diethylaminoethylmethacrylamide, vinylpyrrolidone, vinylsulfonic acid, allylamine, allylglycydylether and the like;
aromatic ionic, non-ionic and reactive derivatives of acrylic, methacrylic, vinylic and allylic compounds, such as vinyltoluene, phenylpropylacrylamide, trimethylaminophenylbutylmethacrylate, tritylacrylamide, and the like; and
heterocyclic ionic, non-ionic and reactive derivatives of acrylic, methacrylic, vinylic and allylic compounds, such as vinylimidazole, vinylpyrrolidone, acryloylmorpholine, and the like.
Co-monomers for obtaining three-dimensional structures are those containing functional groups such as double bonds that react with other monomers during the process of forming the three-dimensional structure. Typical co-monomers include, but are not limited to:
bisacrylamides, such as N,Nxe2x80x2-methylene-bis-acrylamide, N,Nxe2x80x2-ethylene-bis-acrylamide, N, Nxe2x80x2-hexamethylene-bis-acrylamide, glyoxal-bis-acrylamide, and the like;
bis-methacrylamides, such as N,Nxe2x80x2-methylene-bis-methacrylamide, N,Nxe2x80x2-ethylene-bis-methacrylamide, N,Nxe2x80x2-hexamethylene-bis-methacrylamide, and the like;
bis-acrylates, such as N-diethylmethacrylate, dimethylmethacrylate and the like;
ethyleneglycol-methacyletes and the like; and
diallyltartradiamide.
The combination of these monomers and others confers to the three-dimensional polymer a predetermined property, as desired. Properties which are of interest include ion exchange effects, hydrophobic associations, phase partition, biospecific recognition and intermediate or mixed effects of these properties. Internal hydrogels with molecular sieving properties are also contemplated within the scope of this invention.
The invention is further defined by reference to the following examples, which do not limit the scope of the invention, but are given to illustrate and further support what is described above.